1. Field of the Invention
The present invention relates to novel substituted imidazoles, to methods for their preparation, to the use of these compounds as medicaments, to pharmaceutical compositions comprising the compounds, and to a method of treatment employing these compounds and compositions. The present compounds show a high and selective binding affinity to the histamine H3 receptor indicating a histamine H3 receptor antagonistic or agonistic activity. As a result, the compounds are useful for the treatment of disorders related to the histamine H3 receptor. More particularly, the present compounds possess a histamine H3 receptor antagonistic activity and accordingly are useful for the treatment of disorders in which a histamine H3 receptor blockade is beneficial.
2. Description of the Related Art
The histamine H3 receptor is known and of current interest for the development of new medicaments (see e.g. Stark, H.; Schlicker, E.; Schunack, W., Drugs Fut. 1996, 21, 507-520; Leurs, R.; Timmerman, H.; Vollinga, R. C., Progress in Drug Research 1995, 45, 107-165). The histamine H3 receptor is a presynaptic autoreceptor located in both the central and the peripheral nervous system, the skin and in organs such as the lung, the intestine, probably the spleen and the gastrointestinal tract. The histamine H3 receptor has been demonstrated to regulate the release of histamine and also of other neurotransmitters such as serotonin and acetylcholine. A histamine H3 receptor antagonist would therefore be expected to increase the release of these neurotransmitters in the brain. A histamine H3 receptor agonist, on the contrary, leads to an inhibition of the biosynthesis and release of histamine and also of other neurotransmitters such as serotonin and acetylcholine. These findings suggest that histamine H3 receptor agonists and antagonists could be important mediators of neuronal activity. Accordingly, the histamine H3 receptor is an important target for new therapeutics.
Several publications disclose the preparation and use of histamine H3 agonists and antagonists.
Thus, U.S. Pat. No. 4,767,778 (corresponding to EP 214 058), EP 338 939, EP 531 219, EP 458 661, WO 91/17146, WO 92/15567, WO 96/38142 and WO 96/38141 disclose imidazole derivatives having histamine H3 receptor agonistic or antagonistic activity. However, none of these derivatives has a five or six membered carbocyclic ring optionally containing one or two double bonds directly attached to the 4-position of the imidazole ring such as is the case in the present compounds.
WO 93/12093 disclose imidazole derivatives having histamine H3 receptor agonistic or antagonistic activity. These derivatives have a six or seven membered nitrogen containing ring in the 4-position of the imidazole ring which nitrogen containing ring is attached to the imidazole ring via a methylene group. EP 197 840, EP 494 010, WO 95/11894, WO 93/20061, WO 93/12108, WO 93/12107, WO 94/17058 and WO 95106037 disclose imidazole derivatives having histamine H3 receptor agonistic or antagonistic activity. These derivatives have a five or six membered nitrogen containing ring attached to the 4-position of the imidazole ring and thus differ structurally from the present compounds which have a five or six membered carbocyclic ring optionally containing one or two double bonds in the same position.
WO 93/14070 disclose imidazole derivatives having histamine H3 antagonistic activity. These derivatives have a hydrocarbon chain optionally containing one or more heteroatoms attached to the 4-position of the imidazole ring which hydrocarbon chain may bear a cycloalkyl or cycloalkenyl group. U.S. Pat. No. 5,578,616 (corresponding to WO 95/14007) discloses phenyl-alkyl imidazoles as histamine H3 receptor antagonists. These phenyl-alkyl imidazoles differ structurally from the present compounds by having a C1-3-alkylene group inserted between the imidazole ring and the phenyl ring. In the present compounds, on the contrary, the imidazole ring is directly attached to a five or six membered carbocyclic ring optionally containing one or two double bonds.
WO 96/40126 discloses substituted imidazole derivatives having histamine H3 receptor agonistic activity. Some of these may have a cyclohexyl group directly attached to the 4-position of the imidazole ring. However, a nitrogen atom is always attached to the 4-position of the cyclohexyl ring.
Furthermore, WO 98/07718 and Chemical Abstracts, Volume 84, No 11, Mar. 15, 1976, 73197p disclose imidazole derivatives. However, they are not disclosed as histamine H3 receptor agonists or antagonists.
In view of the arts"" interest in histamine H3 receptor agonists and antagonists, novel compounds which trigger the histamine H3 receptor would be a highly desirable contribution to the art. The present invention provides such a contribution to the art being based on the finding that a novel class of substituted imidazole compounds has a high and specific affinity to the histamine H3 receptor and possesses histamine H3 receptor antagonistic activity.
Due to their histamine H3 receptor antagonistic activity the present compounds are useful in the treatment and/or prevention of a wide range of conditions and disorders in which a blockade of the histamine H3 receptor is beneficial. Thus, the compounds may find use, e.g., in the treatment of diseases of the central nervous system, the peripheral nervous system, the cardiovascular system, the pulmonary system, the gastrointestinal system and the endocrinologic system.
Definitions
In the structural formulas given herein and throughout the present specification, the following terms have the indicated meaning:
The term xe2x80x9cC1-6-alkylxe2x80x9d as used herein represents a branched or straight hydrocarbon group having from 1 to 6 carbon atoms. Typical C1-6-alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl and the like.
The term xe2x80x9cC1-6-alkoxyxe2x80x9d as used herein, alone or in combination, refers to the radical xe2x80x94Oxe2x80x941-6-alkyl where C1-6-alkyl is as defined above. Representative examples are methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.
The term xe2x80x9cC1-6-alkylsulfonylxe2x80x9d as used herein, alone or in combination, refers to the radical xe2x80x94S(xe2x95x90O)2xe2x80x94C1-6-alkyl where C1-6-alkyl is as defined above. Representative examples are methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, isopentylsulfonyl, hexylsulfonyl, isohexylsulfonyl and the like.
The term xe2x80x9cC3-8-cycloalkylxe2x80x9d as used herein represents a carbocyclic group having from 3 to 8 carbon atoms. Representative examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
The term xe2x80x9carylxe2x80x9d as used herein is intended to include carbocyclic aromatic ring systems such as phenyl, naphthyl (1-naphthyl or 2-naphthyl), anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), phenanthrenyl, fluorenyl, indenyl and the like. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1-(1,2,3,4-tetrahydronaphthyl) and 2-(1,2,3,4-tetrahydronaphthyl).
The term xe2x80x9carylsulfonylxe2x80x9d as used herein refers to the radical xe2x80x94S(xe2x95x90O)2-aryl where aryl is as defined above. Non-limiting examples are phenylsulfonyl, naphthylsulfonyl, phenanthrenylsulfonyl, fluorenylsulfonyl, indenylsulfonyl and the like.
The term xe2x80x9cheteroarylxe2x80x9d as used herein is intended to include heterocyclic aromatic ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, such as furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, thiadiazinyl, indolyl, isoindolyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl, purinyl, quinazolinyl, quinolizinyl, quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl and the like. Heteroaryl is also intended to include the partially or fully hydrogenated derivatives of the heterocyclic systems enumerated above. Non-limiting examples of such partially or fully hydrogenated derivatives are pyrrolinyl, pyrazolinyl, indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepinyl, diazepinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, oxazolinyl, oxazepinyl, aziridinyl and tetrahydrofuranyl.
The term xe2x80x9chalogenxe2x80x9d means fluorine, chlorine, bromine or iodine.
As used herein, the phrase xe2x80x9c3 to 8 membered, saturated or unsaturated, carbocyclic or heterocyclic ringxe2x80x9d is intended to include carbocyclic rings which are saturated or contain one or more double bonds as well as heterocyclic rings containing one or more heteroatoms selected from nitrogen, oxygen or sulfur which are saturated or contain one or more double bonds.
The term xe2x80x9coptionally substitutedxe2x80x9d as used herein means that the groups in question are either unsubstituted or substituted with one or more of the substituents specified. When the groups in question are substituted with more than one substituent the substituents may be the same or different.
As used herein, the phrase xe2x80x9ca functional group which can be converted to hydrogen in vivoxe2x80x9d is intended to include any group which upon administering the present compounds to the subjects in need thereof can be converted to hydrogen, e.g,. enzymatically or by the acidic environment in the stomach. Non-limiting examples of such groups are acyl, carbamoyl, monoalkylated carbamoyl, dialkylated carbamoyl, alkoxycarbonyl, alkoxyalkyl groups and the like such as C1-6-alkanoyl, aroyl, C1-6-alkylcarbamoyl, di-C1-6-alkylcarbamoyl, C1-6-alkoxycarbonyl and C1-6-alkoxy-C1-6-alkyl.
Certain of the above defined terms may occur more than once in the structural formulas, and upon such occurrence each term shall be defined independently of the other.
The present invention relates to novel substituted imidazoles of formula I 
wherein the carbocyclic ring optionally contains one or two double bonds;
n represents 1 or 2;
R1 is hydrogen or a functional group which can be converted to hydrogen in vivo;
R2 is hydrogen, C1-6-alkyl, cyano or halogen;
R3 is hydrogen, hydroxy or halogen;
R4 is hydrogen, hydroxy or cyano;
R5 is
hydrogen;
aryl optionally substituted with halogen, C1-6-alkoxy, C1-6-alkyl, trifluoromethyl, C3-8-cycloalkyl, aryl or heteroaryl;
C1-6-alkyl optionally substituted with
C3-8-cycloalkyl optionally substituted with halogen, C1-6-alkoxy, C1-6-alkyl, trifluoromethyl, C3-8-cycloalkyl, aryl or heteroaryl;
aryl optionally substituted with halogen, C1-6-alkoxy, C1-6-alkyl, trifluoromethyl, C3-8-cycloalkyl, aryl or heteroaryl; or
heteroaryl optionally substituted with halogen, C1-6-alkoxy, C1-6-alkyl, trifluoromethyl, C3-8-cycloalkyl, aryl or heteroaryl;
xe2x80x94Xxe2x80x94R6 wherein X is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94; and
R6 is
hydrogen;
C1-6-alkyl optionally substituted with halogen, C1-6-alkoxy, trifluoromethyl, C3-8-cycloalkyl, aryl or heteroaryl where the C3-8-cycloalkyl, aryl and heteroaryl groups optionally are substituted with halogen, C1-6-alkoxy, C1-6-alkyl, trifluoromethyl, C3-8-cycloalkyl, aryl or heteroaryl;
C3-8-cycloalkyl optionally substituted with halogen, C1-6-alkoxy, C1-6-alkyl, trifluoromethyl, C3-8-cycloalkyl, aryl or heteroaryl;
aryl optionally substituted with halogen, C1-6-alkoxy, C1-6-alkyl, trifluoromethyl, C3-8-cycloalkyl, aryl or heteroaryl;
heteroaryl optionally substituted with halogen, C1-6-alkoxy, C1-6-alkyl, trifluoromethyl, C3-8-cycloalkyl, aryl or heteroaryl;
xe2x80x94CONR7R8 wherein R7 and R8 independently are
hydrogen;
C1-6-alkyl optionally substituted with halogen, C1-6-alkoxy, trifluoromethyl, C3-8-cycloalkyl, aryl or heteroaryl where the C3-8-cycloalkyl, aryl and heteroaryl groups optionally are substituted with halogen, C1-6-alkoxy, C1-6-alkyl, trifluoromethyl, C3-8-cycloalkyl, aryl or heteroaryl;
C3-8-cycloalkyl optionally substituted with halogen, C1-6-alkoxy, C1-6-alkyl, trifluoromethyl, C3-8-cycloalkyl, aryl or heteroaryl;
aryl optionally substituted with halogen, C1-6-alkoxy, C1-6-alkyl, trifluoromethyl, C3-8-cycloalkyl, aryl or heteroaryl;
heteroaryl optionally substituted with halogen, C1-6-alkoxy, C1-6-alkyl, trifluoromethyl, C3-8-cycloalkyl, aryl or heteroaryl; or
R7 and R8 together form a 3 to 8 membered, saturated or unsaturated carbocyclic or heterocyclic ring which is optionally substituted with halogen, C1-6-alkoxy, C1-6-alkyl, trifluoromethyl, C3-8-cycloalkyl, aryl or heteroaryl; or
xe2x80x94SO2R7 wherein R7 is as defined above;
xe2x80x83with the proviso that when X is xe2x80x94Sxe2x80x94; R6 must not be hydrogen, xe2x80x94CONR7R8 or xe2x80x94SO2R7; or
xe2x80x94CONR7R8 wherein R7 and R8 are as defined above; or
R4 and R5 taken together represent xe2x95x90O;
xe2x80x83with the provisos that
when R2 is hydrogen; R3, R4 or R5 must not be methyl or ethyl in the 1 position;
when n is 2; R1 is xe2x80x94CPh3; R2 and R3 are hydrogen; R4 is cyano in the 1 position; R5 must not be hydrogen;
when n is 2; R1, R2, R3 and R4 are hydrogen; R5 must not be hydrogen;
as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.
In a preferred embodiment the invention relates to compounds of the formula I wherein n is 2.
In another preferred embodiment of the invention the carbocyclic ring is cyclohexyl.
In still another preferred embodiment the invention relates to compounds of the formula I wherein R1 and R2 are both hydrogen.
A further preferred embodiment of the invention relates to compounds of the formula I wherein R3 and R4 are both hydrogen.
A further preferred embodiment of the invention relates to compounds of the formula I wherein R5 is xe2x80x94Xxe2x80x94R6 and n, the carbocyclic ring, R1, R2, R3 and R4 are as defined for formula I and preferably as defined in the preferred embodiments above.
R6 is preferably hydrogen; C1-6-alkyl optionally substituted as defined for formula I; aryl optionally substituted as defined for formula I; or xe2x80x94CONR7R8 wherein R7 and R8 are as defined for formula I.
A particularly preferred group of the compounds of the formula I as defined above are such compounds wherein wherein X is xe2x80x94Oxe2x80x94 and R6 is C1-6-alkyl substituted with phenyl which is optionally substituted with halogen, cyano or trifluoromethyl; phenyl optionally substituted with halogen, cyano or trifluoromethyl; or xe2x80x94CONR7R8 wherein R7 and R8 independently are hydrogen; C1-6-alkyl substituted with phenyl which is optionally substituted with halogen, cyano or trifluoromethyl; or phenyl optionally substituted with halogen, cyano or trifluoromethyl. Preferably, one of R7 and R8 represents hydrogen while the other represents one of the other groups mentioned.
The above ethers offer the advantages of being stable towards hydrolytic cleavage and of being lipophilic which indicates a good blood-brain-barrier penetration.
The compounds of the present invention may have one or more asymmetric centers and it is intended that any optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof are included within the scope of the invention.
Furthermore, geometric isomers may be formed. It is intended that any geometric isomers, as separated, pure or partially purified geometric isomers or mixtures thereof are included within the scope of the invention. Likewise, molecules having a bond with restricted rotation may form geometric isomers. These are also intended to be included within the scope of the present invention.
Furthermore, the compounds of the present invention may exist in different tautomeric forms and it is intended that any tautomeric forms which the compounds are able to form are included within the scope of the present invention.
The present invention also encompasses pharmaceutically acceptable salts of the present compounds. Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts. Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric acids and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric acids and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference. Examples of metal salts include lithium, sodium, potassium, magnesium salts and the like. Examples of ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like.
Also intended as pharmaceutically acceptable acid addition salts are the hydrates which the present compounds are able to form.
The acid addition salts may be obtained as the direct products of compound synthesis. In the alternative, the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
The compounds of the present invention may form solvates with standard low molecular weight solvents using methods known to the skilled artisan. Such solvates are also contemplated as being within the scope of the present invention.
The invention also encompasses prodrugs of the present compounds which on administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances. In general, such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the present compounds. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in xe2x80x9cDesign of Prodrugsxe2x80x9d, ed. H. Bundgaard, Elsevier, 1985.
The invention also encompasses active metabolites of the present compounds.
The compounds of the present invention interact with the histamine H3 receptor and may thus be used for the treatment of a wide range of disorders related to the histamine H3 receptor.
Accordingly, in another aspect the present invention relates to a compound of formula I or any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof for use as a medicament.
The invention also relates to pharmaceutical compositions comprising, as an active ingredient, at least one compound of the formula I or any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers or diluents.
Furthermore, the invention relates to the use of a compound of formula I or any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of disorders related to the histamine H3 receptor.
In still another aspect, the invention relates to a method for the treatment of disorders related to the histamine H3 receptor, the method comprising administering to a subject in need thereof an effective amount of a compound of formula I or any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.
More particularly, the present compounds possess histamine H3 receptor antagonistic activity and are accordingly useful in the treatment of a wide range of conditions and disorders in which a histamine H3 receptor blockade is beneficial.
The compounds of the present invention may thus be used for the treatment of airway disorders such as asthma, as anti-diarrheals and for the modulation of gastric acid secretion.
The compounds of the present invention may also be used for the treatment of diseases associated with the regulation of sleep and wakefulness and for the treatment of narcolepsy and attention deficit disorders.
Moreover, the compounds of the invention may be used as stimulants or as sedatives.
The compounds of the invention may also be useful for the treatment of eating disorders such as binge eating or bulimia by virtue of their appetite regulating properties.
Furthermore, the present compounds may be useful for the treatment and/or prevention of obesity as well as diseases related to obesity, such as diabetes and cardiovascular disorders.
The present compounds may also be used for the treatment of conditions associated with epilepsy. Additionally, the present compounds may be used for the treatment of motion sickness and vertigo. Furthermore, they may be useful as regulators of hypothalamo-hypophyseal secretion, antidepressants, modulators of cerebral circulation, and in the treatment of irritable bowel syndrome.
Further, the compounds of the present invention may be used for the treatment of dementia and Alzheimer""s disease. Moreover, the compounds of the present invention may be used as analgetics and for the treatment of inflammatory painful conditions or neurogenic inflammation.
The present novel compounds may also interact with the vanilloid receptors, the serotonin receptors, and the adrenergic receptors and may be useful for the treatment of diseases associated with these receptors. Hence, the compounds of the present invention may be vanilloid receptor agonists, and thus be useful for the treatment of obesity by enhancement of the metabolic rate and energy expenditure. Further, by virtue of their interaction with the vanilloid receptor the compounds of the present invention may be useful for the treatment of pain or neurogenic inflammation or inflammatory painful conditions.
Furthermore, by virtue of their interaction with the 5-HT3 receptor (serotonin-3-receptor), the compounds of the present invention may be useful as antiemetics, in particular the chemotherapy-induced emesis. Further potential applications of 5-HT3 antagonists include treatment of central nervous system disorders such as anxiety, schizophrenia, drug abuse and withdrawal symptoms, and pathological and age-associated amnesia.
Furthermore, the present compounds may be alpha-2-adrenoceptor agonists or antagonists and thus be useful for the treatment of hypertension and of conditions associated with overexpression or hypersensitization of adrenergic alpha-2 receptors, especially obesity, withdrawal symptoms to an adrenergic alpha-2 agonist, neurological disorders (especially orthostatic hypotension), multiple system atrophy, diabetes mellitus, benign prostatic hyperplasia or drug induced sensitization of adrenergic alpha-2 receptors. Moreover, the compounds of the present invention, by virtue of their interaction with alpha-2 receptors, may be useful as sedatives and hypnotics (sleep inducing agents) or as stimulants.
In a preferred embodiment of the invention the present compounds are used for the preparation of a medicament for the reduction of weight.
In a preferred embodiment of the invention the present compounds are used for the preparation of a medicament for the treatment and/or prevention of overweight or obesity.
In another preferred embodiment of the invention the present compounds are used for the preparation of a medicament for the suppression of appetite or satiety induction.
In a further preferred embodiment of the invention the present compounds are used for the preparation of a medicament for the prevention and/or treatment of disorders and diseases related to overweight or obesity such as atherosclerosis, hypertension, diabetes, especially Type 2 diabetes (NIDDM (non-insulin dependent diabetes mellitus)), dyslipidemia, coronary heart disease, gallbladder disease, osteoarthritis and various types of cancer such as endometrial, breast, prostate and colon cancers.
In yet a further preferred embodiment of the invention the present compounds are used for the preparation of a medicament for the prevention and/or treatment of eating disorders such as bulimia and binge eating.
In a further aspect of the invention the present compounds may be administered in combination with one or more further pharmacologically active substances, e.g., other antiobesity agents or appetite regulating agents.
Such agents may be selected from the group consisting of CART agonists, NPY antagonists, MC4 agonists, orexin antagonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, xcex23 agonists, MSH (melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK agonists, serotonin re-uptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormone, growth hormone releasing compounds, TRH agonists, uncoupling protein 2 or 3 modulators, GLP-1, leptin agonists, DA agonists (bromocriptin, doprexin), lipase/amylase inhibitors, PPAR modulators, RXR modulators or TR xcex2 agonists.
In a preferred embodiment of the invention the antiobesity agent is leptin.
In another preferred embodiment the antiobesity agent is dexamphetamine or amphetamine.
In another preferred embodiment the antiobesity agent is fenfluramine or dexfenfluramine.
In still another preferred embodiment the antiobesity agent is sibutramine.
In a further preferred embodiment the antiobesity agent is orlistat.
In another preferred embodiment the antiobesity agent is mazindol or phentermine.
The present compounds may also be administered in combination with one or more antidiabetics or other pharmacologically active material(s), including compounds for the treatment and/or prophylaxis of insulin resistance and diseases, wherein insulin resistance is the pathophysiological mechanism. Suitable antidiabetics comprise insulin, GLP-1 derivatives such as those disclosed in WO 98/08871 to Novo Nordisk A/S, which is incorporated herein by reference, as well as orally active hypoglycemic agents.
The orally active hypoglycemic agents preferably comprise sulphonylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists such as those disclosed in WO 99/01423 to Novo Nordisk A/S and Agouron Pharmaceuticals, Inc., GLP-1 agonists, potassium channel openers such as those disclosed in WO 97/26265 and WO 99/03861 to Novo Nordisk A/S which are incorporated herein by reference, insulin sensitizers Furthermore, the present compounds may be administered in combination with the insulin sensitizers such as those disclosed in WO 99/19313 to Dr. Reddy""s Research Foundation, DPP-IV inhibitors, inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and/or glycogenolysis, glucose uptake modulators, compounds modifying the lipid metabolism such as antihyperlipidemic agents and antilipidemic agents, compounds lowering food intake, PPAR and RXR agonists and agents acting on the ATP-dependent potassium channel of the xcex2-cells.
In a preferred embodiment of the invention the present compounds are administered in combination with insulin.
In a further preferred embodiment the present compounds are administered in combination with a sulphonylurea, e.g., tolbutamide, glibenclamide, glipizide or glicazide.
In another preferred embodiment the present compounds are administered in combination with a biguanide, e.g., mefformin.
In yet another embodiment the present compounds are administered in combination with a meglitinide, e.g., repaglinide.
In still another preferred embodiment the present compounds are administered in combination with a thiazolidinedione selected from troglitazone, ciglitazone, pioglitazone, rosiglitazone and the compounds disclosed in WO 97/41097 to Dr. Reddy""s Research Foundation, especially 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]-methyl]-2,4-thiazolidinedione.
In a further preferred embodiment the present compounds are administered in combination with an a-glucosidase inhibitor, e.g., miglitol or acarbose.
In yet a preferred embodiment the present compounds are administered in combination with an agent acting on the ATP-dependent potassium channel of the xcex2-cells selected from tolbutamide, glibenclamide, glipizide, glicazide and repaglinide.
Furthermore, the present compounds may be administered in combination with nateglinide.
In still another embodiment the present compounds are administered in combination with an antihyperlipidemic agent or antilipidemic agent, e.g., cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
In a further embodiment the present compounds are administered in combination with more than one of the above-mentioned compounds, e.g., in combination with a sulphonylurea and metformin, a sulphonylurea and acarbose, repaglinide and metformin, insulin and a sulphonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.
Furthermore, the present compounds may be administered in combination with one or more antihypertensive agents. Examples of antihypertensive agents are xcex2-blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and xcex1-blockers such as doxazosin, urapidil, prazosin and terazosin. Further reference can be made to Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995.
It should be understood that any suitable combination of the compounds according to the invention with one or more of the above-mentioned compounds and optionally one or more further pharmacologically active substances are considered to be within the scope of the present invention.
Pharmaceutical Compositions
The compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses. The pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995.
The pharmaceutical compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.
Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings such as enteric coatings or they can be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well-known in the art.
Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also contemplated as being within the scope of the present invention.
Other suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants etc.
A typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferred from about 0.05 to about 10 mg/kg body weight per day administered in one or more dosages such as 1 to 3 dosages. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
The formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art. A typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain of from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, and more preferred from about 0.5 mg to about 200 mg.
For parenteral routes, such as intravenous, intrathecal, intramuscular and similar administration, typically doses are in the order of about half the dose employed for oral administration.
The compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof. One example is an acid addition salt of a compound having the utility of a free base. When a compound according to the invention contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of the compound according to the invention with a chemical equivalent of a pharmaceutically acceptable acid, for example, inorganic and organic acids. Representative examples are mentioned above. Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable cation such as sodium or ammonium ion.
For parenteral administration, solutions of the present compounds in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may be employed. Such aqueous solutions should be suitable buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. The aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene or water. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The pharmaceutical compositions formed by combining the compounds according to the invention and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. These formulations may be in the form of powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion.
If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
A typical tablet which may be prepared by conventional tabletting techniques may contain:
If desired, the pharmaceutical composition of the invention may comprise the compound of the formula I in combination with one or more other pharmacologically active substances.
The preparation of the compounds according to the invention can be realized in many ways.
The synthesis of compounds of formula I, wherein the carbocyclic ring is a six membered carbocyclic ring (Ia, saturated ring; Ib, the ring contains one double bond; Ic, the ring contains two double bonds) (R1 and R2 are as defined for formula I, R3xe2x95x90R4xe2x95x90H, R5xe2x95x90xe2x80x94Oxe2x80x94R6, wherein R6 is as defined for formula I) is sketched below: 
In this synthesis 1-(dimethylaminosulfonyl)-2-(dimethyl-tert-butylsilyl)imidazoles II (R. Ganellin et al., J. Med. Chem. 1996, 39, 3806-3813) are lithiated and then reacted with cyclohexane-1,4-dione monoethyleneketal to give tertiary alcohols III. Other, similarly protected imidazole derivatives may alternatively be used. Acidolytic removal of the protecting groups followed by tritylation yields keto-alcohols IV. These alcohols IV can be used for the preparation of the compounds of formulas Ia, Ib or Ic which form part of the present compounds of formula I.
Thus, treatment of the keto-alcohols IV with methanesulfonyl chloride and triethylamine leads to elimination of water with simultaneous formation of products of formula Icxe2x80x2. Acidolytic removal of the protecting group and optional introduction of the group R1 leads to the formation of products Ic wherein R6 is xe2x80x94SO2CH3.
Reduction of the products resulting from elimination of water with a reducing agent such as sodium borohydride leads to the formation of alcohols Ibxe2x80x2, which can be used as starting materials for the preparation of compounds of formulas Iaxe2x80x2 and Ib.
Compounds of formula Iaxe2x80x2 can be prepared by hydrogenation of Ibxe2x80x2.
Compounds of formula Ib can be prepared by chemical transformation of the hydroxy group in the alcohols Ibxe2x80x2 into a group xe2x80x94OR6 and conversion of the trityl group into the group R1.
Conversion of the alcohols Iaxe2x80x2 into compounds of formula Ia is analogous to the conversion of Ibxe2x80x2 into Ib.
Alternatively, compounds Ia may be prepared by hydrogenation of Ib, if the groups R1 and R6 are stable towards the hydrogenation conditions.
The conversion of the hydroxy group of Iaxe2x80x2 or Ibxe2x80x2 into the group xe2x80x94OR6 can be achieved using conventional synthetic methodology. For instance, alkylation of the hydroxy group of alcohols Iaxe2x80x2 or Ibxe2x80x2 with alkyl halides or alkyl sulfonic esters (Williamson ether synthesis) yields alkyl ethers (R6=primary or secondary substituted or unsubstituted alkyl). Mitsunobu etherification can be used for the preparation of arylethers (R6=substituted or unsubstituted aryl). Reaction of the alcohols Iaxe2x80x2 or Ibxe2x80x2 with isocyanates or carbamoyl chlorides yields carbamates (urethanes) (R6=xe2x80x94CONR7R8 wherein R7 and R8 are as defined for formula I). Conversion of the trityl group into a group R1 can be realized by acid catalyzed detritylation (Trxe2x86x92H), optionally followed by introduction of a chemically labile group R1, such as an acyl group or a carbamoyl group, by conventional methods.
In yet another aspect, the present invention relates to a process for the preparation of a compound of formula Id 
wherein X, R1, R2 and R6 are as defined for formula I, as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof comprising the steps of
reducing a 4-(4-oxocyclohex-1-enyl)imidazole derivative of the formula V 
wherein P is an appropriate protecting group such as trityl, with a suitable reducing agent such as sodium borohydride to give a 4-(4-hydroxycyclohex-1-enyl)imidazole derivative of the formula Ibxe2x80x2
wherein P and R2 are as defined above,
hydrogenating said derivative of the formula Ibxe2x80x2 with a suitable hydrogenating agent such as hydrogen and a catalyst such as platinum to give a 4-(4-hydroxycyclohexyl)imidazole derivative of the formula Iaxe2x80x2
wherein P and R2 are as defined above, and then
i) when X is oxygen and R6 is hydrogen: deprotecting the derivative of the formula Iaxe2x80x2 to give a compound of formula Id wherein R1 is hydrogen and, if necessary, introducing a labile functional group to give a compound of formula Id wherein R1 is a functional group which can be converted to hydrogen in vivo, and, if appropriate, separating the compound of formula Id into its diastereomeric or enantiomeric forms and, if desired, converting the compound of formula Id into a salt with a pharmaceutically acceptable acid,
ii) when X is oxygen and R6 is C1-6-alkyl, C3-8cycloalkyl, aryl or heteroaryl which are optionally substituted as defined for formula I: etherifying said derivative of formula Iaxe2x80x2 with R6-Hal wherein R6 has the above meanings and Hal represents halogen and deprotecting the resulting derivative to give a compound of formula Id wherein R1 is hydrogen and, if necessary, introducing a labile functional group to give a compound of formula Id wherein R1 is a functional group which can be converted to hydrogen in vivo, and, if appropriate, separating the compound of formula Id into its diastereomeric or enantiomeric forms and, if desired, converting the compound of formula Id into a salt with a pharmaceutically acceptable acid,
iii) when X is oxygen and R6 is xe2x80x94CONR7R8 wherein R7 and R8 are as defined for formula I: reacting the derivative of formula Iaxe2x80x2 with Clxe2x80x94COxe2x80x94NR7R8 or Oxe2x95x90Cxe2x95x90Nxe2x80x94R7 wherein R7 and R8 have the above meaning and deprotecting the resulting derivative to give a compound of formula Id wherein R1 is hydrogen and, if necessary, introducing a labile functional group to give a compound of formula Id wherein R1 is a functional group which can be converted to hydrogen in vivo, and, if appropriate, separating the compound of formula Id into its diastereomeric or enantiomeric forms and, if desired, converting the compound of formula Id into a salt with a pharmaceutically acceptable acid,
iv) when X is oxygen and R6 is xe2x80x94SO2R7 wherein R7 is as defined for formula I: reacting the derivative of formula Iaxe2x80x2 with Clxe2x80x94SO2xe2x80x94R7 wherein R7 has the above meaning and deprotecting the resulting derivative to give a compound of formula Id wherein R1 is hydrogen and, if necessary, introducing a labile functional group to give a compound of formula Id wherein R1 is a functional group which can be converted to hydrogen in vivo, and, if appropriate, separating the compound of formula Id into its diastereomeric or enantiomeric forms and, if desired, converting the compound of formula Id into a salt with a pharmaceutically acceptable acid,
v) when X is sulfur and R6 is C1-6-alkyl, C3-8-cycloalkyl, aryl or heteroaryl which are optionally substituted as defined for formula I: substituting the hydroxy group by R6xe2x80x94SH wherein R6 has the above meanings and deprotecting the resulting derivative to give a compound of formula Id wherein R1 is hydrogen and, if necessary, introducing a labile functional group to give a compound of formula Id wherein R1 is a functional group which can be converted to hydrogen in vivo, and, if appropriate, separating the compound of formula Id into its diastereomeric or enantiomeric forms and, if desired, converting the compound of formula Id into a salt with a pharmaceutically acceptable acid.
Compounds of formula Id wherein X is oxygen and R6 is aryl or heteroaryl which are optionally substituted as defined for formula I may alternatively be prepared by nucleophilic substitution of the hydroxy group of the compounds of formula Iaxe2x80x2 by the corresponding aromatic alcohols and heteroaromatic alcohols, respectively.
The starting compound of formula V may be obtained by the treatment of the compound of formula IV with methanesulfonyl chloride and triethylamine to eliminate water as explained above in connection with the general reaction scheme.